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“The only thing necessary for these diseases to the triumph is for good people and governments to do nothing.”

       

Treatment of Hepatitis B

http://www.medscape.com/viewarticle/434534

 

Geoffrey L. Braden, MD   

Introduction

Hepatitis B remains a major worldwide public health problem. Globally, there are 350 million carriers of the hepatitis B virus (HBV) vs 370 million carriers of the hepatitis C virus (Hepatitis C Virus). In the United States, 4.0 million persons are positive for Hepatitis C Virus antibodies and 2.7 million of these individuals are chronic carriers, with positive Hepatitis C Virus polymerase chain reaction (PCR) assays.[1] In comparison, it is estimated that 1.25 million carriers of hepatitis B are present in the United States. Although hepatitis C may be associated with a higher incidence of chronic hepatitis compared with hepatitis B, and may lead to cirrhosis in 20% to 25% of patients, chronic hepatitis B leads to chronic hepatitis and cirrhosis in 15% to 20% of carriers, and is associated with an even higher incidence of hepatocellular carcinoma (HCC) in asymptomatic carriers than is hepatitis C.

The hepatitis B virus is carcinogenic in chronic carriers without objective evidence of liver disease. The yearly risk of HCC in asymptomatic hepatitis B carriers is 0.47%. The incidence of HCC in hepatitis B-related cirrhosis is 2% to 6% per year, similar to the incidence of HCC in Hepatitis C Virus-related and other forms of cirrhosis. This tendency for the HBV to induce hepatic carcinogenesis accounts for the fact that HCC is one of the leading forms of cancer in China and Southeast Asia. Asymptomatic carriers of HBV should be screened yearly, using serum alpha feto-protein studies and liver ultrasound to look for HCC. Although definitive studies are lacking, HBV patients with cirrhosis should be screened every 6 months with a serum alpha feto-protein test and an ultrasound of the liver. This screening protocol affords the best opportunity to diagnose small HCCs that can be treated for cure with either a segmental hepatic resection of the involved area or with liver transplantation. Currently, liver transplantation is reserved for patients with HCC who have 3 tumors, all < 3.0 cm in size, or a single tumor </= 5 cm in size. Palliative treatment may also be improved with earlier diagnosis of HCC, although again, screening has not been shown to decrease mortality in series of patients with HBV and other chronic liver diseases.

This year's Digestive Disease Week meeting provided several excellent sessions to refine our knowledge of the diagnosis and treatment of hepatitis B. Robert Perrillo, MD, presented an American Association for the Study of Liver Diseases (AASLD)-sponsored state-of-the-art lecture on the treatment of hepatitis B. An AASLD topic forum on hepatitis B was presented on May 19, and an AASLD poster session on hepatitis B was held on May 21. Jenny Heathcote, MD, and K. Rajender Reddy, MD, also contributed their expertise during luncheon breakout sessions.

This review addresses the natural history of chronic hepatitis B and the clinical subtypes of carriers of hepatitis B, and discusses the emerging importance of genotyping in defining subclasses of patients, including those at risk for precore/core promoter variants and HCC. The treatment of hepatitis B with interferon, lamivudine, and other nucleoside analogues used alone and in combination is also addressed, as is the use of lamivudine in patients with decompensated cirrhosis. Finally, the treatment of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis (precore/core promoter variants) is discussed.

    

Subtypes of Hepatitis B Carriers

Hepatitis B Surface Antigen (HBsAg)-Positive Adult Carriers

This form of HBV is the most common subtype found in the United States. Infection occurs via blood transfusions (mostly before 1976), intravenous-drug use, sexual transmission, and via horizontal transmission from living with a carrier of hepatitis B (3%-6% risk). HIV-positive patients who are on hemodialysis are also at risk. Patients are usually HBeAg-negative and anti-HBe-positive when the diagnosis is made. These patients usually have normal liver enzyme levels and quiescent inflammation on liver biopsy. Once HBeAg seroconversion takes place, the virus shifts from a replicative stage to an integrated form, and whatever degree of chronic hepatitis that was present becomes inactive. HBV DNA is usually negative by hybridization assays, which is the preferable study for the evaluation and management of patients with chronic hepatitis B. The branched DNA assay (Bayer), hybrid capture assay (Digene), and liquid hybridization assay (Abbott) are sensitive down to 100,000-1,000,000 copies/mL.[2] A negative HBV DNA on hybridization assay defines the inactive carrier state. All of these patients will be positive for HBV DNA when more sensitive PCR assays such as the Amplicor assay (Roche) are used. Some of these assays are positive down to 100-400 copies/mL. Generally, patients with < 1,000,000 copies/mL of HBV virus do not have active liver disease. The latter represents a distinct difference from our management of viral loads and the standard use of the PCR assay in patients with chronic hepatitis C. The exception to this rule is the management of HBeAg-negative chronic hepatitis, which will be discussed separately.

Manno and colleagues[3] followed 296 asymptomatic HBsAg-positive blood donors from France for 30 years. Thirty-two percent of these patients spontaneously lost HBsAg over that time period. Most of the patients had normal liver enzymes, and a control group was followed. The hepatitis B carriers had the same overall and liver-related mortality as the control group.

Neonatal Hepatitis B

Chronic hepatitis B is an endemic infection in Southeast Asia and the South Pacific. Fifty percent or more of HBV infection is spread by perinatal transmission.[2] Patients remain immunotolerant of the virus as neonates and through early childhood. Longstanding persistence of HBeAg is present and seroconversion occurs later in adulthood. Many of these patients have high HBV DNA levels as infants but achieve normal liver function tests as children. These patients often develop HBeAg-positive chronic hepatitis B with elevated liver enzymes in adulthood. These patients are an important reservoir for those who go on to subsequently develop cirrhosis and HCC. The majority of these patients will spontaneously seroconvert as adults to the HBeAg-negative, anti-HBe-positive state. Even though this transition occurs, considerable liver injury may have already taken place.

Recently, I observed an Asian American patient who had contracted neonatal hepatitis B from his mother who herself had emigrated to the United States from Taiwan. He is in his late 20s, has normal liver enzymes, is HBsAg-positive, HBeAg-negative, and anti-HBe-positive. His HBV DNA assays are negative by hybridization, but he has established cirrhosis on liver biopsy (Geoffrey L. Braden, MD, 2002; personal observation). In this case, the damage was caused by chronic hepatitis B infection years before this patient presented to me. As more individuals with chronic hepatitis B emigrate from Southeast Asia to the United States, this type of problem is likely to become more prevalent.

HBV Infection in Patients From Sub-Saharan Africa, Alaska, and the Mediterranean

In these countries, hepatitis B is usually transmitted horizontally from person to person during childhood. Perinatal transmission is less common. Most of these children have elevated alanine aminotransferase (ALT) levels. HBeAg seroconversion occurs around puberty.

Hepatitis B e Antigen-Negative Chronic Hepatitis B

These patients have precore and core promoter mutations and represent an emerging group of patients with chronic hepatitis B who have active liver disease. Precore variants involve a G1896A mutation and core promoter variants involve A1762T and G1764A mutations in HBV DNA polymerase. These variants arrest the production of HBeAg during viral replication. These patients are HBsAg-positive, HBeAg-negative, and anti-HBe-positive. They have elevated liver enzymes, chronic liver disease, and relatively low levels of circulating HBV DNA. Although hybridization assays for HBV DNA are usually positive in this subgroup, a PCR assay may occasionally be necessary to quantify the amount of virus that is present. These patients represent a subgroup that is relatively resistant to treatment with interferon or lamivudine. It is also important to remember that although HBeAg synthesis does not occur, the majority of these patients are anti-HBe-positive. This subgroup is differentiated from the inactive carrier who has a similar serologic profile by the fact that elevated aminotransferases (> 2x normal) are present, along with active liver disease on liver biopsy. Commercial assays for these mutations are available to help define this subset. The prevalence of these mutations ranges from 20% to 90% among patients originating from Europe and the Mediterranean, 10% to 38% among those from Asia and the South Pacific, and is approximately 10% among those in the United States.[4]

Use of Genotyping in Hepatitis B

The use of genotyping will increase in the future in order to help define different subtypes of patients. The precore mutation is more common with genotype D, which is more prevalent in the Mediterranean, and is rare in patients with genotype A, which is the most common genotype in the Unites States and Western Europe.

Chu and colleagues[5] looked at the distribution of genotypes in the US population; all 7 known HBV genotypes were found in this country. The majority of Americans were found to have genotypes A and C (67% combined), but there are regional and ethnic differences in the nationwide breakdown. The precore variant was also found to be more prevalent in genotype D patients. The core promoter variant was more common in genotypes C and D. Genotype D patients showed a higher incidence for developing decompensated cirrhosis.

Chien and colleagues[6] looked at variables that affected a sustained response (HBeAg seroconversion) to lamivudine therapy in a group of Taiwanese patients. Using a stepwise regression model that examined many clinical variables, only genotype was found to be the predictor of a sustained response to lamivudine. Sixty-one percent and 14% of patients with genotypes B and C, respectively, had a sustained response. In a related paper, Watanabe and associates[7] looked at the association between genotype and the development of HCC in a group of 100 patients followed for 11 years. Seventy-four percent of their patients were genotype C and 26% were genotype B; HCC developed in 25 patients. Genotype C, along with age, lower platelet counts, and higher gamma-glutamyltranspeptidase (GGTP) levels were associated with a greater risk of HCC. Although the number of patients followed in this study was small, it is possible that genotyping will be used routinely in the future in the setting of hepatitis B to help define subgroups of patients at risk for the development of HCC who will respond to treatment. In contrast to hepatitis C, at present, there are no reliable data on the response of HBV to interferon or lamivudine therapy based on genotype.

    

Treatment of Chronic Hepatitis B

The goals of treatment are to decrease or eliminate viral replication and improve histology, by decreasing the amount of inflammation present, and either stabilizing or reversing fibrosis. Other goals are to prevent the development of HCC and to prolong life.

Interferon Therapy

In the early 1990s, interferon was approved for the treatment of hepatitis B in the United States. The standard dose is 5 million units daily or 10 million units 3 times per week given subcutaneously for a total of 16 weeks. Patients treated should have aminotransferase levels that are > 2x elevated, be HBeAg-positive, and have chronic hepatitis on liver biopsy. The United States Food and Drug Administration (FDA) has approved the use of interferon in patients with serum aminotransferases > 5x normal, but the consensus is that patients with aminotransferases > 2x normal should be evaluated for treatment because they have a significant incidence of chronic hepatitis on liver biopsy and also a significant likelihood of responding to treatment.

A treatment response is defined as normalization of liver enzymes, loss of HBV DNA by hybridization assay, and loss of HBeAg with or without conversion to anti-HBe positivity. A sustained viral response is defined as maintaining this improvement for 6 months beyond the end of treatment. Forty percent of patients with aminotransferases between 100 and 200 U/L and 50% with aminotransferases > 200 will normalize serum ALT on treatment. Sixty-seven percent of patients with aminotransferases between 100 and 200 U/L and close to 100% of those with aminotransferases > 200 will develop undetectable HBV DNA on treatment.[4] Thirty-seven percent of patients will develop a sustained loss of HBV DNA, 33% a sustained loss of HBeAg, and 8% will lose HBsAg over time. Liver function tests often flare during treatment because the interferon triggers an immunologic clearance of the virus. This event can cause acute hepatic decompensation in patients with cirrhosis. Patients with advanced cirrhosis should be treated with lamivudine. Pegylated interferon is now being studied for the treatment of chronic hepatitis B.

Cooksley and colleagues[8] looked at a 24-week course of pegylated interferon alfa-2a compared with regular interferon alfa-2a. Twelve percent of patients who received short-acting interferon, compared with 27% to 28% of patients who were treated with 90 or 180 mcg per week of pegylated interferon, achieved a sustained response, as defined by loss of HBeAg, undetectable HBV DNA by hybridization assay, and ALT normalization. Pegylated interferon may be one of the treatment approaches of the future. Ribavirin, which is used in hepatitis C regimens, does not have any activity against hepatitis B.

Lebensztejn and colleagues[9] looked at the sustained response to short-acting interferon alfa given to 71 children with chronic hepatitis B. Thirty-two of 71 (45%) developed a sustained response to 3 million units of interferon alfa given 3 times per week for 20 weeks. The patients were followed for 36 months and all of the responses were durable. All patients had negative HBV DNA assays and maintained their seroconversion to anti-HBe.

Nucleoside Analog Therapy

Lamivudine was approved by the FDA for the treatment of chronic hepatitis B in 1999. The approved dose is 100 mg/day given orally for 1 year. Clinical trials[10] have shown response rates at 1 year that include a 32% loss of HBeAg and a 17% seroconversion rate. Almost all patients initially become HBV DNA-negative on treatment. Treatment beyond 1 year is both controversial and problematic.

In one study of long-term therapy in Asian patients,[11] the HBeAg conversion rate was 47% after 4 years of continued lamivudine treatment. Improvement in fibrosis occurs in patients with cirrhosis and bridging fibrosis. Asians and whites respond similarly to lamivudine therapy. Patients with aminotransferases > 2x normal are candidates for treatment. Patients with aminotransferases > 5x normal clear HBeAg in 50% to 60% of cases with 1 year of treatment, compared with 25% to 30% of patients with aminotransferases between 2x-5x that of normal. This finding is similar to that observed with interferon, in which case the response is better if the patient has aminotransferases increased > 5x normal. The incidence of lamivudine resistance increases proportionately with the duration of treatment. YMDD-resistant mutations in HBV DNA polymerase develop in 20%, 38%, 49%, and 66% after 1,2,3, and 4 years of continued treatment.[12,13] YMDD resistance is generally associated with lower HBV DNA levels and lower aminotransferase elevations compared with before treatment. However, the long-term natural history of YMDD-resistant mutants is unknown in patients who have been treated with lamivudine. Although generally these mutants do not cause a major reactivation of chronic hepatitis B, fulminant hepatitis has been reported.[14] On the other hand, emergence of YMDD mutants can be associated with continued control of the disease. I am currently treating a patient with HBV-induced polyarteritis nodosa who presented with abdominal pain, peripheral neuropathy, hypertension, and significant renal failure. He has been on lamivudine for 20 months. Fourteen months into treatment, he developed YMDD-resistant mutants, with a rise in his HBV DNA from nondetectable to 14,000,000 copies/mL. He has not developed a recurrence of his disease. Presumably, the lamivudine is still suppressing the wild-type hepatitis virus, which caused the vasculitis initially (Geoffrey L. Braden, 2002; personal observation).

Adefovir dipivoxil is currently under review by the FDA for treatment of wild-type and lamivudine-resistant chronic hepatitis B. It has in vitro and in vivo activity against wild-type and YMDD variants. The dose is 10 mg, given once daily. It appears to be effective and no resistance has been reported out to 136 weeks of treatment.[4,15,16] Adefovir can cause renal insufficiency and is contraindicated in patients with chronic renal failure. Entecavir is another nucleoside analog under study for the treatment of chronic hepatitis B. It is a potent inhibitor of HBV DNA polymerase and is also active against wild-type virus and lamivudine-resistant YMDD mutations.

Lamivudine can be given to patients with decompensated cirrhosis due to chronic hepatitis B. It has been reported to increase albumin levels, decrease bilirubin levels, decrease Child-Pugh scores, prolong survival, and possibly delay the need for liver transplantation.[4] Future strategies may use adefovir and lamivudine in combination to treat patients in this setting. Trials are currently in progress using short-acting interferon or pegylated interferon in combination with lamivudine. The preliminary results of these studies appear promising. Other nucleoside analogues under study for treatment of chronic hepatitis B include famciclovir, emtricitabine, and tenofovir. Lim and colleagues[17] presented a phase 2 dose-ranging study of Val-LdC, an L-nucleoside agent with activity against hepatitis B. Patients were treated for 28 days and achieved a 3.6-log10 drop in HBV viral loads.

Treatment of HBeAg-Negative Chronic Hepatitis B

The response to treatment in patients with precore/core promoter mutations is not predicted by baseline ALT or HBV DNA levels. HBV DNA levels are lower in these patients than in patients with wild-type virus, and it may be necessary to use PCR assays to follow the response to treatment. If interferon is used, patients should be treated for at least 12 months. When lamivudine is employed, there is a high rate of relapse in patients who respond to 1 year of therapy. Treatment beyond 1 year may be necessary, but is of unproven value. The natural history of YMDD mutants developing in patients with precore/core promoter variants treated with lamivudine is unknown. Better treatment for this subgroup is a subject of major clinical investigation.

Conclusion

More effective therapy is needed for the treatment of patients with chronic hepatitis B. Current therapies produce a complete cure (loss of HBsAg) in only 8% to 10% of patients. The current goals of treatment are to produce HBeAg seroconversion, which usually results in a significant improvement in liver histology and may slow or prevent the development of cirrhosis. Currently, candidates for treatment include patients with aminotransferases > 2x normal, chronic hepatitis on liver biopsy, HBV DNA levels > 100,000 by hybridization assay, and HBeAg positivity. The future is bright for the development of new nucleoside analogs that will be used alone or in combination with interferon or other nucleoside agents, in a manner similar to that currently employed to treat other chronic viral diseases, such as HIV.

References

  1. Alter M, Kruszon-Moran D, Wainan OU, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-562.
  2. Lok SF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225-1241.
  3. Manno M, Grottola A, Ferretti I, et al. Natural history of chronic asymptomatic HBV infection: survival analysis after thirty years. Gastroenterology. 2002;122:A-627. [Abstract #85]
  4. Perrillo R. Hepatitis B: Treatment, AASLD State-of-the-Art Lecture. Program and abstracts of Digestive Disease Week 2002; May 19-22, 2002; San Francisco, California. [Sp419]
  5. Chu CJ, Keefe EB, Han SH, et al. HBV Genotypes in the United States-Results of a nation-wide study. Gastroenterology. 2002;122:A-627. [Abstract #86]
  6. Chien RN, Liaw YF, Tsai SL. HBV genotype is the major factor for durability of HBeAg response to lamivudine therapy. Gastroenterology. 2002;122:P-216. [Poster #T1359]
  7. Watanabe H, Enomoto N, Ikeda T, et al. Association between HBV genotype and development of hepatocellular carcinoma. Gastroenterology. 2002;122:P-215. [Poster # T1354]
  8. Cooksley GE, Piratvisuth T, Wang YJ, et al. 40 KDA Peginterferon alpha 2a (Pegasys): Efficacy and safety results from a phase II, randomized, actively controlled, multicenter trial in the treatment of HBeAg positive chronic hepatitis B. Hepatology. 2001;34:349:710A.
  9. Lebensztejn DM, Kaczmarski M, Sinkiewicz J, et al. Long term evaluation of children with chronic hepatitis B after HBeAg/Anti-HBe seroconversion caused by interferon alpha treatment. Gastroenterology. 2002;122:A-303. [Poster #M1448]
  10. Dienstag, JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341:1256-1263.
  11. Chang TT, Lai CL, Liaw YF, et al. Incremental increases in HBeAg seroconversion and continued ALT normalization in Asian chronic HBV (CHB) patients treated with lamivudine for four years. Antivir Ther. 2000;5(suppl 1):44A.
  12. Leung NWY, Lai CL, Chang TT, et al. Extended lamivudine treatment in patients with chronic hepatitis B enhances hepatitis B e antigen seroconversion rates: results after 3 years of therapy. Hepatology. 2001;33:1527-1532.
  13. Liaw YF, Leung NWY, Chang TT, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Gastroenterology. 2000;119:172-180.
  14. Wang JH, Lu SN, Lee CM, et al. Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis. Scand J Gastroenterol. 2002;37:366-369.
  15. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil (ADV) 10 mg for the treatment of chronic hepatitis B. Gastroenterology. 2002;122:P-216. [Poster #T1366]
  16. Peters M, Schiff E, Benhamou Y, et al. Adefovir dipivoxil (ADV) demonstrates viral efficacy and clinical benefit in the treatment of lamivudine resistant (LAM-R) chronic HBV: An analysis of four clinical trials. Gastroenterology. 2002;122:P-216. [Poster # T1367]
  17. Lim, SG, Lai CL, Dan YY, et al. Val-LdC: First evidence of efficacy and safety for a new anti-HBV agent. Gastroenterology. 2002;122:A-628. [Abstract #87]